tbuckley/cabot-search huggingface dataset:
Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors
Authors: Jessica B Foster, Crystal Griffin, Jo Lynne Rokita, Allison Stern, Cameron Brimley, Komal Rathi, Maria V Lane, Samantha N Buongervino, Tiffany Smith, Peter J Madsen, Daniel Martinez, Alberto Delaidelli, Poul H Sorensen, Robert J Wechsler-Reya, Katalin Karikó, Phillip B Storm, David M Barrett, Adam C Resnick, John M Maris, Kristopher R Bosse
Journal: Journal for ImmunoTherapy of Cancer (2022)

Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.
Helen Salisbury: A poor plan for patients
Authors: Helen Salisbury
Journal: BMJ (2022)

<h3>Background and Objectives</h3> Most studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) have been cross-sectional. The few longitudinal studies have not accounted for potential heterogeneity in HRQOL trajectories. There may be groups of individuals with common physical or mental HRQoL trajectories over time. Identification of early risk factors for membership in trajectories with poor HRQoL would inform on those at risk. We aimed to identify physical and mental HRQoL trajectories among people with MS and early risk factors for membership in the trajectory groups with the worst HRQoL. <h3>Methods</h3> Between 2004 and 2020, we queried NARCOMS participants regarding HRQoL using the RAND-12, demographics, fatigue, and physical impairments (using the Patient-Determined Disease Steps scale). We included participants who were enrolled in the NARCOMS registry within 3 years of MS diagnosis, lived in the United States, reported physician-confirmed MS, and had ≥3 HRQoL observations. We used group-based trajectory modeling to determine whether there were distinct clusters of individuals who followed similar HRQoL trajectories over time. We evaluated whether baseline participant characteristics associated with the probability of trajectory group membership using a multinomial logit model. <h3>Results</h3> We included 4,888 participants who completed 57,564 HRQoL questionnaires between 1 and 27 years after MS diagnosis. Participants had a mean (SD) age of 41.7 (9.5) years at diagnosis, and 3,978 participants (81%) were women. We identified 5 distinct physical HRQoL trajectories and 4 distinct mental HRQoL trajectories. Older age at diagnosis, worse physical impairments, and worse fatigue were associated with an increased odds of being in the group with the worst physical HRQoL when compared with being in the other 4 groups. Income ≤$50,000 and no postsecondary education were associated with an increased odds of membership in the group with the lowest mental HRQoL when compared with that in the other 3 groups. <h3>Discussion</h3> We identified groups of people with MS who reported similar physical and mental HRQoL trajectories over time. There are early risk factors for membership in the groups with the worst HRQoL that are easily identifiable by clinicians, providing an opportunity for early interventions.
False gene and chromosome losses in genome assemblies caused by GC content variation and repeats
Authors: Juwan Kim, Chul Lee, Byung June Ko, Dong Ahn Yoo, Sohyoung Won, Adam M. Phillippy, Olivier Fedrigo, Guojie Zhang, Kerstin Howe, Jonathan Wood, Richard Durbin, Giulio Formenti, Samara Brown, Lindsey Cantin, Claudio V. Mello, Seoae Cho, Arang Rhie, Heebal Kim, Erich D. Jarvis
Journal: Genome biology (2022)

Abstract Background Many short-read genome assemblies have been found to be incomplete and contain mis-assemblies. The Vertebrate Genomes Project has been producing new reference genome assemblies with an emphasis on being as complete and error-free as possible, which requires utilizing long reads, long-range scaffolding data, new assembly algorithms, and manual curation. A more thorough evaluation of the recent references relative to prior assemblies can provide a detailed overview of the types and magnitude of improvements. Results Here we evaluate new vertebrate genome references relative to the previous assemblies for the same species and, in two cases, the same individuals, including a mammal (platypus), two birds (zebra finch, Anna’s hummingbird), and a fish (climbing perch). We find that up to 11% of genomic sequence is entirely missing in the previous assemblies. In the Vertebrate Genomes Project zebra finch assembly, we identify eight new GC- and repeat-rich micro-chromosomes with high gene density. The impact of missing sequences is biased towards GC-rich 5′-proximal promoters and 5′ exon regions of protein-coding genes and long non-coding RNAs. Between 26 and 60% of genes include structural or sequence errors that could lead to misunderstanding of their function when using the previous genome assemblies. Conclusions Our findings reveal novel regulatory landscapes and protein coding sequences that have been greatly underestimated in previous assemblies and are now present in the Vertebrate Genomes Project reference genomes.
Inspiratory Effort and Respiratory Mechanics in Patients with Acute Exacerbation of Idiopathic Pulmonary fibrosis: A Preliminary Matched Control Study
Authors: R. Tonelli, I. Castaniere, A. Cortegiani, L. Tabbì, R. Fantini, D. Andrisani, F. Gozzi, A. Moretti, G. Bruzzi, L. Manicardi, C. Cerbone, C. Nani, E. Biagioni, S. Cerri, V. Samarelli, S. Busani, M. Girardis, A. Marchioni, E. Clini
Journal: Pulmonology (2022)

Patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) may experience severe acute respiratory failure, even requiring ventilatory assistance. Physiological data on lung mechanics during these events are lacking. Patients with AE-IPF admitted to Respiratory Intensive Care Unit to receive non-invasive ventilation (NIV) were retrospectively analyzed. Esophageal pressure swing (ΔPes) and respiratory mechanics before and after 2 hours of NIV were collected as primary outcome. The correlation between positive end-expiratory pressure (PEEP) levels and changes of in dynamic compliance (dynCRS) and PaO2/FiO2 ratio was assessed. Further, an exploratory comparison with a historical cohort of ARDS patients matched 1:1 by age, sequential organ failure assessment score, body mass index and PaO2/FiO2 level was performed. At baseline, AE-IPF patients presented a high respiratory drive activation with ΔPes = 27 (21–34) cmH2O, respiratory rate (RR) = 34 (30–39) bpm and minute ventilation (VE) = 21 (20–26) L/min. Two hours after NIV application, ΔPes, RR and VE values showed a significant reduction (16 [14–24] cmH2O, p<0.0001, 27 [25–30] bpm, p=0.001, and 18 [17–20] L/min, p=0.003, respectively) while no significant change was found in dynamic transpulmonary pressure, expiratory tidal volume (Vte), dynCRS and dynamic mechanical power. PEEP levels negatively correlated with PaO2/FiO2 ratio and dynCRS (r=–0.67, p=0.03 and r=–0.27, p=0.4, respectively). When compared to AE-IPF, ARDS patients presented lower baseline ΔPes, RR, VE and dynamic mechanical power. Differently from AE-IPF, in ARDS both Vte and dynCRS increased significantly following NIV (p=0.01 and p=0.004 respectively) with PEEP levels directly associated with PaO2/FiO2 ratio and dynCRS (r=0.24, p=0.5 and r=0.65, p=0.04, respectively). In this study, patients with AE-IPF showed a high inspiratory effort, whose intensity was reduced by NIV application without a significant improvement in respiratory mechanics. In an exploratory analysis, AE-IPF patients showed a different mechanical behavior under spontaneous unassisted and assisted breathing compared with ARDS patients of similar severity.
Nanometer- and angstrom-scale characteristics that modulate complement responses to nanoparticles
Authors: S. Moein Moghimi, Hajira B. Haroon, Anan Yaghmur, Dmitri Simberg, Panagiotis N. Trohopoulos
Journal: Journal of Controlled Release (2022)

The contribution of the complement system to non-specific host defence and maintenance of homeostasis is well appreciated. Many particulate systems trigger complement activation but the underlying mechanisms are still poorly understood. Activation of the complement cascade could lead to particle opsonisation by the cleavage products of the third complement protein and might promote inflammatory reactions. Antibody binding in a controlled manner and/or sensing of particles by the complement pattern-recognition molecules such as C1q and mannose-binding lectin can trigger complement activation. Particle curvature and spacing arrangement/periodicity of surface functional groups/ligands are two important parameters that modulate complement responses through multivalent engagement with and conformational regulation of surface-bound antibodies and complement pattern-recognition molecules. Thus, a better fundamental understanding of nanometer- and angstrom-scale parameters that modulate particle interaction with antibodies and complement proteins could portend new possibilities for engineering of particulate drug carriers and biomedical platforms with tuneable complement responses and is discussed here.
Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment
Authors: Angela M. Araujo, Andrea Abaurrea, Peio Azcoaga, Joanna I. López-Velazco, Sara Manzano, Javier Rodriguez, Ricardo Rezola, Leire Egia-Mendikute, Fátima Valdés-Mora, Juana M. Flores, Liam Jenkins, Laura Pulido, Iñaki Osorio-Querejeta, Patricia Fernández-Nogueira, Nicola Ferrari, Cristina Viera, Natalia Martín-Martín, Alexandar Tzankov, Serenella Eppenberger-Castori, Isabel Alvarez-Lopez, Ander Urruticoechea, Paloma Bragado, Nicholas Coleman, Asís Palazón, Arkaitz Carracedo, David Gallego-Ortega, Fernando Calvo, Clare M. Isacke, María M. Caffarel, Charles H. Lawrie
Journal: Journal of Clinical Investigation (2022)
What can the UK learn from the EU’s covid plan for winter 2022-23?
Authors: Samantha Field, Martin McKee
Journal: BMJ (2022)

This winter is likely to be brutal.The rising cost of living will force many people to choose whether to "heat or eat."And, despite optimism expressed by several eminent figures, 1 2 it's clear that the covid-19 pandemic is not over.England continues to record almost 30 000 cases each week despite vastly reduced testing, with almost 4000 people admitted to hospital. 3It would be very surprising if covid proved to be unlike all respiratory viruses and cases didn't increase further in the winter months.This will inevitably place an already struggling NHS under even more pressure.In these circumstances it's perhaps surprising that, beyond the promise of booster vaccinations, covid-19 is largely lacking from Our Plan for Patients, 4 published by England's new secretary of state for health and social care, Thérèse Coffey.This contrasts with the stance taken by the European Union, which has published a comprehensive plan to counter this persistent threat, 5 which in turn holds lessons for the UK.
Ageing and degeneration analysis using ageing-related dynamic attention on lateral cephalometric radiographs
Authors: Zhiyong Zhang, Ningtao Liu, Zhang Guo, Licheng Jiao, Aaron Fenster, Wenfan Jin, Yuxiang Zhang, Jie Chen, Chunxia Yan, Shuiping Gou
Journal: npj Digital Medicine (2022)

With the increase of the ageing in the world's population, the ageing and degeneration studies of physiological characteristics in human skin, bones, and muscles become important topics. Research on the ageing of bones, especially the skull, are paid much attention in recent years. In this study, a novel deep learning method representing the ageing-related dynamic attention (ARDA) is proposed. The proposed method can quantitatively display the ageing salience of the bones and their change patterns with age on lateral cephalometric radiographs images (LCR) images containing the craniofacial and cervical spine. An age estimation-based deep learning model based on 14142 LCR images from 4 to 40 years old individuals is trained to extract ageing-related features, and based on these features the ageing salience maps are generated by the Grad-CAM method. All ageing salience maps with the same age are merged as an ARDA map corresponding to that age. Ageing salience maps show that ARDA is mainly concentrated in three regions in LCR images: the teeth, craniofacial, and cervical spine regions. Furthermore, the dynamic distribution of ARDA at different ages and instances in LCR images is quantitatively analyzed. The experimental results on 3014 cases show that ARDA can accurately reflect the development and degeneration patterns in LCR images.
Complications and treatment errors in periodontal therapy in medically compromised patients
Authors: Yago Leira, Hana Cho, Debora Marletta, Marco Orlandi, Pedro Diz, Navdeep Kumar, Francesco D’Aiuto
Journal: Periodontology 2000 (2022)

Patients who are medically compromised may be at an increased risk of complications and treatment errors following periodontal therapy. A review of the evidence on the topic is presented, in relation to the type of complication reported, of periodontal treatment, and of patients' medical status. Further, a framework for risk assessment and appropriate treatment modifications is introduced, with the aim of facilitating the management of patients with existing comorbidities and reducing the incidence of treatment complications.
Clinical and patient‐reported outcomes of tissue engineering strategies for periodontal and peri‐implant reconstruction
Authors: Lorenzo Tavelli, Shayan Barootchi, Giulio Rasperini, William V. Giannobile
Journal: Periodontology 2000 (2022)

Scientific advancements in biomaterials, cellular therapies, and growth factors have brought new therapeutic options for periodontal and peri-implant reconstructive procedures. These tissue engineering strategies involve the enrichment of scaffolds with living cells or signaling molecules and aim at mimicking the cascades of wound healing events and the clinical outcomes of conventional autogenous grafts, without the need for donor tissue. Several tissue engineering strategies have been explored over the years for a variety of clinical scenarios, including periodontal regeneration, treatment of gingival recessions/mucogingival conditions, alveolar ridge preservation, bone augmentation procedures, sinus floor elevation, and peri-implant bone regeneration therapies. The goal of this article was to review the tissue engineering strategies that have been performed for periodontal and peri-implant reconstruction and implant site development, and to evaluate their safety, invasiveness, efficacy, and patient-reported outcomes. A detailed systematic search was conducted to identify eligible randomized controlled trials reporting the outcomes of tissue engineering strategies utilized for the aforementioned indications. A total of 128 trials were ultimately included in this review for a detailed qualitative analysis. Commonly performed tissue engineering strategies involved scaffolds enriched with mesenchymal or somatic cells (cell-based tissue engineering strategies), or more often scaffolds loaded with signaling molecules/growth factors (signaling molecule-based tissue engineering strategies). These approaches were found to be safe when utilized for periodontal and peri-implant reconstruction therapies and implant site development. Tissue engineering strategies demonstrated either similar or superior clinical outcomes than conventional approaches for the treatment of infrabony and furcation defects, alveolar ridge preservation, and sinus floor augmentation. Tissue engineering strategies can promote higher root coverage, keratinized tissue width, and gingival thickness gain than scaffolds alone can, and they can often obtain similar mean root coverage compared with autogenous grafts. There is some evidence suggesting that tissue engineering strategies can have a positive effect on patient morbidity, their preference, esthetics, and quality of life when utilized for the treatment of mucogingival deformities. Similarly, tissue engineering strategies can reduce the invasiveness and complications of autogenous graft-based staged bone augmentation. More studies incorporating patient-reported outcomes are needed to understand the cost-benefits of tissue engineering strategies compared with traditional treatments.
NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy
Authors: Matthias Pinter, David J. Pinato, Pierluigi Ramadori, Mathias Heikenwalder
Journal: Clinical Cancer Research (2022)

Abstract The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)—a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC). Preliminary data from preclinical studies suggest that immunotherapy efficacy may be reduced in NASH-related HCC compared with viral HCC; however, conclusive evidence supporting clinical translation of these findings is lacking. Comprehensive clinical and immunologic phenotyping of mechanisms linking NASH progression with carcinogenesis and therapeutic resistance is key to prevent progression to cirrhosis, improve monitoring and stratification of NASH according to predicted cancer risk, and ultimately increase survival of patients with NASH-HCC. In this review, we summarize the state of the art in the field of NASH and NASH-HCC with focus on immunobiology. We discuss preclinical and clinical findings underpinning NASH as an immunologically distinct pro-tumorigenic disease entity, and explore areas of potential therapeutic vulnerabilities in NASH-associated HCC.
HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells
Authors: Priya Pai, Guannan Wang, Wei Wen Teo, Diana Raez-Rodriguez, Kathleen L. Gabrielson, Balázs Győrffy, Bradley M. Downs, Akanksha Aggarwal, Saraswati Sukumar
Journal: Cancer Research (2022)

Abstract HOXA5 is a transcription factor and tumor suppressor that promotes differentiation of breast epithelial cells and is frequently lost during malignant transformation. HOXA5 loss alone, however, does not confer tumorigenicity. To determine which molecular alterations combined with loss of HOXA5 expression can transform cells, we examined isogenic derivatives of a nonmalignant breast epithelial cell line containing knock-in or knockout mutations in key breast cancer genes. Knockdown (KD) of HOXA5 in cells harboring double knock-in (DKI) of mutated PIK3CA (E545K) and HER2 (V777L) induced epithelial–mesenchymal transition and migration and promoted invasive tumor outgrowth within mouse mammary ducts. The NF-κB pathway was significantly upregulated in DKI cells following HOXA5 KD. HOXA5 KD upregulated multiple NF-κB target genes, including IL6. IκBα protein, but not RNA, expression was reduced in HOXA5-KD cells. HOXA5 bound and stabilized IκBα, forming a nuclear HOXA5-IκBα complex. Chromatin immunoprecipitation sequencing database queries revealed that HOXA5 and IκBα are co-enriched at 528 genomic loci. In patients with breast cancer, high coexpression of HOXA5 and IκBα conferred a significantly better overall and progression-free survival. Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα. Significance: Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.
Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis
Authors: Junya Tabata, Takashi Nakaoku, Mitsugu Araki, Ryunosuke Yoshino, Shinji Kohsaka, Ayaka Otsuka, Masachika Ikegami, Ayako Ui, Shin-ichiro Kanno, Keiko Miyoshi, Shigeyuki Matsumoto, Yukari Sagae, Akira Yasui, Masakazu Sekijima, Hiroyuki Mano, Yasushi Okuno, Aikou Okamoto, Takashi Kohno
Journal: Cancer Research (2022)

Abstract Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations. Significance: Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.